US4812555AExpiredUtility
Peptides possessing renin inhibitory activity

Assignee: MERCK PATENT GMBHPriority: Oct 31, 1985Filed: Mar 22, 1988Granted: Mar 14, 1989
Est. expiryOct 31, 2005(expired)· nominal 20-yr term from priority
Inventors:Peter Raddatz Gunter Holzemann Alfred Jonczyk Claus J. Schmitges Klaus-Otto Minck
Y10S530/86A61P 9/12C07D 233/64C07K 5/0227C07K 5/00A61P 43/00
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Claims
Abstract

New peptides of the formula I X--Z--NR.sup.2 --CHR.sup.3 --CHOH--(CHR.sup.4).sub.n --CO--E wherein X, Z, R 2 , R 3 , R 4 , E and n are as defined herein and their salts inhibit the activity of human plasma renin.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. A peptide compound of the formula I   X--Z--NR.sup.2 --CHR.sup.3 --CHOH--(CHR.sup.4).sub.n --CO--E I     wherein   X is H, R 1  --O--C m  H 2m  --CO--, R 1  --C m  H 2m  --O--CO--, R 1  --C m  H 2m  --CO--, R 1  --SO 2  --, (R 1  --C m  H 2m )-- L(R 1  --C p  H 2p )--C r  H 2r  --CO--, H--(NHCH 2  CH 2 ) m  -- NH--CH 2  CO-- or 9-fluorenyl-C m  H 2m  --O--CO--,   Z is 1 to 4 amino acid radicals which are bonded to one another in peptide form and chosen independently from Abu, Ada, Ala, Arg, Asn, Bia, Cal, Dab, Gln, Gly, His, N(im)-alkyl-His, Ile, Leu, tert.-Leu, Lys, Met, α-Nal, βNal, Nbg, Nle, Orn, Phe, Pro, Ser, Thr, Tic, Trp, Tyr, and Val, is OH, OA, NH 2 , NHA or NA 2 ,   R 1  is H, A, Ar, Ar-alkyl, cycloalkyl which has 3 to 7 C atoms and is unsubstituted or mono- or polysubstituted by alkyl, alkoxy and/or Hal, cycloalkyl-alkyl with 4-11 C atoms, bicycloalkyl or tricycloalkyl with in each case 7-14 C atoms or bicycloalkylalkyl or tricycloalkylalkyl with in each case 8-18 C atoms, wherein the group (R 1  -- C m  H 2m )--L(R 1  --C p  H 2p ) also can be pyrrolidino, piperidino, morpholino or thiomorpholino,   R 2  and R 4  are each independently H or A,   R 3  is cycloalkylalkyl, bicycloalkylalkyl or tricycloalkylalkyl with in each case up to 18 C atoms,   L is CH or N,   m, p and r are each independently, 0, 1, 2, 3, 4 or 5,   n is 1 or 2,   Ar is phenyl, naphthyl or phenyl substituted by A, AO, Hal, CF 3 , OH or NH 2 ,   Hal is F, Cl, Br or I and   A is alkyl of 1-8 C atoms, wherein one or more --NH--CO-- groups can be replaced by --N(alkyl)--CO-- groups, and wherein A and Hal groups can be the same or different, or a pharmaceutically acceptable salt thereof with the proviso that     E is OH, Oalkyl of 5-8 C atoms, NHA or NA 2   when at the same time     Z is (Pro) x  -Y,   x is 0 or 1,   Y is Phe-Phe, Phe-His, Phe-Leu, Phe-Tyr, Phe-Nle, His-Phe, His-His, His-Leu, His-Tyr, His-Nle, Leu-Phe, Leu-His, Leu-Leu, Leu-Tyr, Leu-Nle, Tyr-Phe, Tyr-His, Tyr-Leu, Tyr-Tyr, Tyr-Nle, αNal-Phe, αNal-His, αNal-Leu, αNal-Tyr or αNal-Nle,   R 2  and R 4  are each H,   R 3  is cycloalkylalkyl with 5-10 C atoms, and   n is 1.   
     
     
       2. A compound of claim 1, wherein A is an alkyl of 1-4 C atoms. 
     
     
       3. A compound of claim 1, wherein Ar is phenyl. 
     
     
       4. A compound of claim 1, wherein R 1  is A. 
     
     
       5. A compound of claim 1, wherein R 2  and R 4  are each independently H or methyl. 
     
     
       6. A compound of claim 1, wherein R 3  is cyclohexylmethyl. 
     
     
       7. A compound of claim 1, wherein m, p and r are independently 0, 1 or 2 and n is 1. 
     
     
       8. A compound of claim 1, wherein X is H, POA, BOC, CBZ, acetyl, propionyl, butyryl, isobutyryl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, phenylacetyl, 2- or 3-phenylpropionyl, 4-phenylbutyryl, 2-benzyl-3-phenylpropionyl, 2-benzyl-4-phenylbutyryl, 2-(2-phenylethyl)-4-phenylbutyryl, 2-(2-naphthylmethyl)-4-phenylbutyryl, 2 or 3-o-, -m- or -p-fluorophenylpropionyl, 2- or 3-o-, -m- or -p-chlorophenylpropionyl, cyclohexylacetyl or 2- or 3-cyclohexylpropionyl, wherein POA is phenoxyacetyl, BOC is tert.-butoxycarbonyl and CBZ is benzyloxycarbonyl.   
     
     
       9. A compound of claim 1, wherein Z is His, Phe-His, Pro-Phe-His or His-Pro-Phe-His. 
     
     
       10. A compound of claim 1, wherein Z is Abu, Ada, Asn, Bia, Cal, Gln, N-(im)-alkyl-His, Leu, αNal, βNal, Nle, Phe, Trp, Tyr, Abu-His, Ada-His, Ala-His, Ala-Phe, Arg-His, Asn-His, Bia-His, Cal-His, Dab-His, Gly-His, His-His, Ile-His, Leu-His, tert.-Leu-His, Lys-His, Met-His, αNal-His, βNal-His, Nbg-His, Nle-His, (N-Me-His)-His, (N-Me-Phe)-His, Orn-His, Phe-Abu, Phe-Ada, Phe-Ala, Phe-Arg, Phe-Asn, Phe-Bia, Phe-Cal, Phe-Dab, Phe-Gln, Phe-Gly, Phe-(N-im-alkyl-His), Phe-Ile, Phe-Leu, Phe-tert.-Leu, Phe-Lys, Phe-Met, Phe-α-Nal, Phe-βNal, Phe-Nbg, Phe-Nle, Phe-(N-Me-His), Phe-(N-Me-Phe), Phe-Orn, Phe-Phe, Phe-Pro, Phe-Ser, Phe-Thr, Phe-Tic, Phe-Trp, Phe-Tyr, Phe-Val, Pro-His, Ser-His, Thr-His, Tic-His, Trp-His, Tyr-His, Val-His, Ada-Phe-His, Pro-Ala-His, Pro-Ala-Phe, Pro-Phe-Ala, Pro-Phe-Phe, His-Pro-Ala-His, His-Pro-Ala-Phe, His-Pro-Phe-Ala, His-Pro-Phe-Phe, Pro-Abu-His, Pro-Ada-His, Pro-Arg-His, Pro-Asn-His, Pro-Bia-His, Pro-Dab-His, Pro-Gly-His, Pro-His-His, Pro-Ile-His, Pro-Leu-His, Pro-tert.-Leu-His, Pro-Lys-His, Pro-Met-His, Pro-Nbg-His, Pro-Nle-His, Pro-(N-Me-His)-His, Pro-(N-Me-Phe)-His, Pro-Orn-His, Pro-Phe-Abu, Pro-Phe-Ada, Pro-Phe-Arg, Pro-Phe-Asn, Pro-Phe-Bia, Pro-Phe-Dab, Pro-Phe-Gln, Pro-Phe-Gly, Pro-Phe-(N-im-alkyl-His), Pro-Phe-Ile, Pro-Phe-Leu, Pro-Phe-tert.-Leu, Pro-Phe-Lys, Pro-Phe-Met, Pro-Phe-Nbg, Pro-Phe-Nle, Pro-Phe-(N-Me-His), Pro-Phe-(N-Me-Phe), Pro-Phe-Orn, Pro-Phe-Pro, Pro-Phe-Ser, Pro-Phe-Thr, Pro-Phe-Tic, Pro-Phe-Trp, Pro-Phe-Tyr, Pro-Phe-Val, Pro-Pro-His, Pro-Ser-His, Pro-Thr-His, Pro-Tic-His, Pro-Trp-His, Pro-Tyr-His, Pro-Val-His, His-Pro-Abu-His, His-Pro-Ada-His, His-Pro-Arg-His, His-Pro-Asn-His, His-Pro-Bia-His, His-Pro-Dab-His, His-Pro-Gly-His, His-Pro-His-His, His-Pro-Ile-His, His-pro-Leu-His, His-Pro-tert.-Leu-His, His-Pro-Lys-His, His-Pro-Met-His, His-Pro-Nbg-His, His-Pro-Nle-His, HiS-Pro-(N-Me-His)-His, His-Pro-(N-Me-Phe)-His, His-Pro-Orn-His, His-Pro-Phe-Abu, His-Pro-Phe-Ada, His-Pro-Phe-Arg, His-Pro-Phe-Asn, His-Pro-Phe-Bia, His-Pro-Phe-Dab, His-Pro-Phe-Gln, His-Pro-Phe-Gly, His-Pro-Phe(N-im-alkyl-His), His-Pro-Phe-Ile, His-Pro-Phe-Leu, His-Pro-Phe-tert.-Leu, His-Pro-Phe-Lys, His-Pro-Phe-Met, His-Pro-Phe-Nbg, His-Pro-Phe-Nle, His-Pro-Phe-(N-Me-His), His-Pro-Phe-(N-Me-Phe), His-Pro-Phe-Orn, His-Pro-Phe-Pro, His-Pro-Phe-Ser, His-Pro-Phe-Thr, His-Pro-Phe-Tic, His-Pro-Phe-Trp, His-Pro-Phe-Tyr, His-Pro-Phe-Val, His-Pro-Pro-His, His-Pro-Ser-His, His-Pro-Thr-His, His-Pro-Tic-His, His-Pro-Trp-His, His-Pro-Tyr-His or His-Pro-Val-His. 
     
     
       11. A compound of claim 1, wherein E is OH, OCH 3 , OC 2  H 5 , NH 2 , NHCH 3  or N(CH 3 ) 2 . 
     
     
       12. A compound of claim 1, wherein --NR 3  --CHR 3  --CHOH--(CHR 4 ) n  --CO-- is --NH--CHR 3  --CHOH-- CH 2  --CO--, --NH--CH(cyclohexylmethyl)--CHOH--CH 2  --CO-- or --NH--CH-- (CH 2  CH 2  -cyclohexyl)--cyclohexyl)--CHOH--CH 2  --CO--. 
     
     
       13. A compound of claim 1, wherein X is H, phenoxyacetyl, tert.-butoxycarbonyl, 4-phenylbutyryl, 2-benzyl-3-phenylpropionyl, 2-benzyl-4-phenylbutyryl, 2-(2-phenylethyl)-4-phenylbutyryl, 2-(2-naphthylmethyl)-4-phenylbutyryl or benzyloxycarbonyl,   Z is His, Ada-His, Cal-His, Nle-His, Phe-Abu, Phe-Dab, Phe-His, Phe-Lys, Phe-Met, Phe-(N-im-methyl)-His, Phe-Nle, Phe-Orn, Pro-Phe-His or His-Pro-Phe-His,   R 2  and R 4  are each H,   R 3  is cyclohexylmethyl or 2-cyclohexylethyl,   E is OH, OCH 3 , OC 2  H 5 , NH 2 , NH(CH 3 ) or N(CH 3 ) 2  and   n is 1.   
     
     
       14. A compound of claim 1, wherein X is H, tert.-butoxycarbonyl, 2-benzyl-3-phenylpropionyl, 2-benzyl-4-phenylbutyryl, 2-(2-phenylethyl)-4-phenylbutyryl, or 2-(2-naphthylmethyl)-4-phenylbutyryl,   Z is His, Ada-His, Cal-His, Nle-His, Phe-Abu, Phe-Dab, Phe-His, Phe-Lys, Phe-Met, Phe-(N-im-methyl)-His, Phe-Nle, Phe-Orn,   R 2  and R 4  are each H,   R 3  is cyclohexylmethyl,   E is OH, OCH 3 , OC 2  H 5 , NH 2 , NH(CH 3 ) or N(CH 3 ) 2  and   n is 1.   
     
     
       15. A compound of claim 1, wherein X is H, tert.-butoxycarbonyl or 2-benzyl-4-phenylbutyryl,   Z is His, Phe-Nle or Phe-His,   R 2  and R 4  are each H,   R 3  is cyclohexylmethyl,   E is OH, OCH 3 , OCH 5 , NH 2 , NH(CH 3 ) or N(CH 3 ) 2  and   n is 1.   
     
     
       16. A compound of claim 1, wherein X is tert.-butoxycarbonyl or 2-benzyl-4-phenylbutyryl,   Z is His, Phe-Nle or Phe-His,   R 2  and R 4  are each H,   R 3  is cyclohexylmethyl,   E is OH, OCH 3 , NH 2  or N(CH 3 ) 2  and   n is 1.   
     
     
       17. A compound of claim 1, wherein X is tert.-butoxycarbonyl or 2-benzyl-4-phenylbutyryl,   Z is Phe-Nle or Phe-His,   R 2  and R 4  are each H,   R 3  is cyclohexylmethyl,   E is OH or OCH 3  and   n is 1.   
     
     
       18. A compound of claim 1, wherein X is pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl or thiomopholinocarbonyl.   
     
     
       19. (a) 4-(BOC-Phe-His-amino)-5-cyclohexyl-3-hydroxypentanoic acid; (b) 4-(BOC-Phe-Nle-amino)-5-cyclohexyl-3-hydroxypentanoic acid; or   (c) 5-Cyclohexyl-3-hydroxy-4-(2-benzyl-4-phenylbutyryl-His-amino)-pentanoic acid, wherein BOC is tert.-butoxycarbonyl, and each is a compound of claim 1.     
     
     
       20. A pharmaceutical composition comprising a compound of claim 1, and a compatible carrier. 
     
     
       21. A composition of claim 20, wherein the amount of said compound is about 500 mg to 5 g. 
     
     
       22. A method of treating or preventing hypertension comprising administering a compound of claim 1. 
     
     
       23. A method of treating or preventing hyperaldosteronism comprising administering a compound of claim 1. 
     
     
       24. A method of treating or preventing a disease contributed to by renin, comprising administering a compound of claim 1.
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